In spite of our understanding of KSHV pathogenesis and the implementation of rationally designed therapies based on these advances, advanced KS is mostly an incurable disease and many of the most promising new therapies continue to have major roadblocks and implementation problems in the setting of ART. We have shown that 1) KSHV lytic genes; and particularly the vGPCR oncogene can induce- PDGF mediated activation of PDGFRA and that this is the most prominently activated RTK in AIDS-KS and it is an oncogenic driver and a therapeutic target in KS. 2) We identified PDGFRA (+) mesenchymal stem cells as KS progenitors; and PDGFRA, as an enabler of KSHV oncogenesis in an angiogenic KS like environment and we developed of a new KSHV infection-to-tumorigenesis system that allows to dissect the effect of the angiogenic microenvironment and the contribution of viral and host mechanisms to oncogenesis 3) We found that the ability of the virus to regulate the oxygen sensing machinery allowed the virus to coopt the hypoxia-regulated alternative translation initiation machinery eIF4EH activated by HIF2a and mediated by eIF4E2 alternative cap-binding. This was essential for KSHV replication, for escaping the viral shut-off and for PDGFRA driven pathogenesis in MSCs. The importance of this discovery is that through its regulation of the oxygen sensing machinery the virus access to translation initiation plasticity, defined as the ability for KSHV to alternatively initiate protein synthesis using both the initiation complex eIF4E bearing a cap-binding regulated by the PI3K- AKT-mTOR -HIF1a (eIF4E1 cap-binding) axis or the eIF4EH (eIF4E2 cap-binding) regulated by the HIF2a. We hypothesize that this provides the virus with several adaptive advantages that we will study: 1) Allows the virus to maximize replication in different oxygen levels corresponding to variety of tissues and pathophysiological conditions and it may allow the virus to bypass the stress and innate immunity-related kinases targeting eIF2a inhibition 2) It may be employed by viral oncogenes such as vGPCR and/or by its host-cell signaling mediators such as PDGFRA for proliferation and the induction of direct and paracrine oncogenesis 3) Could allow the transformed host cell to be plastic and adaptive in the context of AIDS-KS therapies targeting PDGFRA such as Imatinib, which are known to target the PDGFRA-AKT-mTOR-E1-HIF1a pathway. We will employ the MSC based de novo oncogenesis to tumorigenesis models, an induction reactivation model and two natural infections systems and AIDS-KS samples from different repositories to test these hypotheses. Aim 1: Study how KSHV regulation of the oxygen sensing machinery (O2SM) leading to HIF2a activation of translational initiation by eIF4EH contributes to KSHV replication and innate immunity evasion. Aim 2: Study mechanisms whereby KSHV regulation of the oxygen sensing machinery leading to HIF2a activation of translational initiation by eIF4EH contributes to KSHV oncogenesis in mouse MSC and human MSCs. Aim 3: Role of translation initiation plasticity in mediating resistance to PDGFRA targeted therapies.